: Evidence now suggests that autoimmune T cells specific to self-determinants use a set of widely shared TcR receptors. This "public" repertoire to self-Ag, as defined by its TcRs, can be targeted for regulation by CD4+ and CD8+ T cells (TREG), which recognize processed TcR from the pathogenic effector T cells (TEFF). Here, the pathogenic and regulatory T cells will be identified and expanded, respectively, in models of multiple sclerosis (relapsing-EAE, an induced model in the SJL mouse), and Type I diabetes (a spontaneous model in the NOD). Public repertoires to candidate autoantigenic determinants and potential regulatory determinants will be defined by TcR CDR3 length spectratyping, also known as "immunoscope" analysis. In conjunction with specific immunization regimens to putative autoantigens, this analysis will define the public TEFF in SJL and NOD mice. These studies will permit the synthesis of potential regulatory peptides, scTcR, and DNA vaccines designed to elicit an anti-TEFF response. In relapsing EAE, a sequential pattern of response and remission to a succession of well-defined pathogenic determinants will aid in the identification of the public clonotypes. The NOR mouse, of identical MHC but resistant to diabetes, and its F1 with NOD, will be used to elucidate pathogenic (and regulatory) populations by employing cyclophosphamide to neutralize the regulation in the NOR and R1. Various approaches to enhance the appearance of regulatory T cells will be used. In total, these studies will demonstrate whether therapeutic induction of TREG with specificity for the processed TcRs of a public repertoire of TEFF can prevent disease, and if such processes are a natural part of effective immune regulation.